title: Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration-controlled trial.
abstract: BACKGROUND
  Fixed-dose mycophenolate mofetil (MMF) reduces the incidence of acute rejection after solid organ transplantation. The Fixed-Dose Concentration Controlled trial assessed the feasibility and potential benefit of therapeutic drug monitoring in patients receiving MMF after de novo renal transplant.
  
  
  METHODS
  Patients were randomized to a concentration-controlled (n=452; target exposure 45 mg hr/L) or a fixed-dose (n=449) MMF-containing regimen. The primary endpoint was treatment failure (a composite of biopsy-proven acute rejection [BPAR], graft loss, death, or MMF discontinuation) by 12 months posttransplantation.
  
  
  RESULTS
  Mycophenolic acid (MPA) exposures for both groups were similar at most time points and were below 30 mg hr/L in 37.3% of patients at day 3. There was no difference in the incidence of treatment failure (25.6% vs. 25.7%, P=0.81) or BPAR (14.9% vs. 15.5%, P>0.05) between the concentration-controlled and the fixed-dose groups, respectively. We did find a significant relationship between MPA-area under the concentration-time curve on day 3 and the incidence of BPAR in the first month (P=0.009) or in the first year posttransplantation (P=0.006). For later time points (day 10, month 1) there was no significant relationship between area under the concentration-time curve and BPAR (0.2572 and 0.5588, respectively).
  
  
  CONCLUSIONS
  There was no difference in the incidence of treatment failure between the concentration-controlled and the fixed-dose groups. The applied protocol of MMF dose adjustments based on target MPA exposure was not successful, partly because physicians seemed reluctant to implement substantial dose changes. Current initial MMF doses underexpose more than 35% of patients early after transplantation, increasing the risk for BPAR.
authors.affiliation: 1Department of Hospital Pharmacy, Erasmus Medical Center, Rotterdam, The Netherlands. t.vangelder@erasmusmc.nl
authors.forename: Teun
authors.initials: T
authors.lastname: van Gelder
authors.forename: Helio Tedesco
authors.initials: HT
authors.lastname: Silva
authors.forename: Johan W
authors.initials: JW
authors.lastname: de Fijter
authors.forename: Klemens
authors.initials: K
authors.lastname: Budde
authors.forename: Dirk
authors.initials: D
authors.lastname: Kuypers
authors.forename: Gunnar
authors.initials: G
authors.lastname: Tyden
authors.forename: Aleksander
authors.initials: A
authors.lastname: Lohmus
authors.forename: Claudia
authors.initials: C
authors.lastname: Sommerer
authors.forename: Anders
authors.initials: A
authors.lastname: Hartmann
authors.forename: Yann
authors.initials: Y
authors.lastname: Le Meur
authors.forename: Michael
authors.initials: M
authors.lastname: Oellerich
authors.forename: David W
authors.initials: DW
authors.lastname: Holt
authors.forename: Burkhard
authors.initials: B
authors.lastname: Tönshoff
authors.forename: Paul
authors.initials: P
authors.lastname: Keown
authors.forename: Scott
authors.initials: S
authors.lastname: Campbell
authors.forename: Richard D
authors.initials: RD
authors.lastname: Mamelok
mesh_terms: D000293:Adolescent; D000328:Adult; D001291:Attitude of Health Personnel; D004334:Drug Administration Schedule; D016903:Drug Monitoring; D004359:Drug Therapy, Combination; D005240:Feasibility Studies; D005260:Female; D006084:Graft Rejection / Q000209:etiology / Q000517:prevention & control*; D006085:Graft Survival / Q000187:drug effects*; D006801:Humans; D007166:Immunosuppressive Agents / Q000008:administration & dosage* / Q000009:adverse effects / Q000493:pharmacokinetics; D016030:Kidney Transplantation / Q000009:adverse effects; D008297:Male; D008875:Middle Aged; D009173:Mycophenolic Acid / Q000008:administration & dosage / Q000009:adverse effects / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D010818:Practice Patterns, Physicians'; D011446:Prospective Studies; D017211:Treatment Failure; D016896:Treatment Outcome
chemical_list: D007166:Immunosuppressive Agents; D009173:Mycophenolic Acid